April 15, 2019
Deep in the inner ear, at the base of the semicircular canals, sit tiny vestibular organs called crista ampullaris – or crista, for short. Aided by millions of sensory hair cells, crista help us maintain our gaze as we move through space, not unlike a stabilizer function in a modern camera. Without a healthy population of these hair cells, the brain struggles to remain oriented and to track its position relative to the surrounding world that our eyes and ears perceive.
Although we commonly associate structures in the inner ear with hearing, not balance, this spatial impairment – imagine vertigo, all the time – contributes to another pervasive health concern for aging adults: falling
In the United States alone, falls lead to more than three million ER visits and 800,000 hospitalizations each year, pushing total medical costs to more than $50 billion. Compounded by weakening bones, falls are a major cause of hip fractures and traumatic brain injuries, often turning-point life events for the aging that compromise mobility, productivity, and independence.
Currently, however, the crista remains understudied, leaving tantalizing questions about the nature of these critical organs and the hair cells that we lose as we age – and that we seem to miss only when they are gone.
Dr. Olivia Bermingham-McDonogh, a Professor of Biological Structure, and a Faculty Member in the UW Medicine Institute for Stem Cell and Regenerative Medicine (ISCRM) is determined to change that.
“The crista are very inaccessible,” explains Dr. Bermingham-McDonogh. “So we know much less about them than we do about the cochlea, for example. We need more data that will help us understand how these structures work and especially about the hair cells within them.”
Two injections of funding have helped fuel the quest to study the crista.
Two years ago, Dr. Bermingham-McDonogh received an Innovation Pilot Award (IPA) through an early-funding program supported by the State of Washington. The IPA allowed her team to gather the preliminary data needed to pursue a multiyear grant that would, in turn, sustain a major research project.
“The IPA was absolutely critical,” says Dr. Bermingham-McDonogh. “It gave us the ability to staff our lab and pursue our passion in the initial, sometimes tenuous, stages of our research. Just as importantly, it was a huge statement from the community that the questions we are asking matter.”
Propelled by the IPA, Dr. Bermingham-McDonogh set out to secure the multiyear funding required to sustain her work. Affirmation arrived this month in the form of a major R01 grant from the NIH, a fifty-fold return on investment for UW, and a testament to the importance of seeding novel research.
Dr. Bermingham-McDonogh and her lab are now focused on answering the million-dollar question: is it possible to regenerate the sensory hair cells that help us stay upright and healthy?
To do that, they are zooming in on single cells – an ongoing sequencing effort, happening in partnership with Dr. Cole Trapnell, Assistant Professor of Genome Sciences – that involves tagging genetic material with microscopic barcodes. “We separate the tissue into single cells, then look closely at the mRNA,” says Dr. Bermingham-McDonogh. “That allows us to see what genes are expressed and what role each cell is actually playing.”
In fact, there are at least two types of cells in the crista – the sensory hair cells that are critical for balance, and support cells which can give rise to the hair cells, under certain circumstances. The gradual loss of hair cells over a lifetime suggests that regenerative capacity fades as we grow older.
Dr. Bermingham-McDonogh suspects that’s not quite true. They have observed in mice that a signaling system known as the Notch pathway is active in certain regions – but, not all regions – of adult crista. Furthermore, blocking the Notch pathway appears to help support cells become hair cells.
The hypothesis? “We think there is a subset of support cells that retains the ability to generate sensory cells,” says Dr. Bermingham-McDonogh. “We are looking for the population of cells that decreases over time when we block the Notch pathway.”
And by studying why some cells populations become depleted, the research team may be able to identify a population of cells that do retain the ability to regenerate, and, crucially, to understand why.
While Dr. Bermingham-McDonogh is perhaps breaking new ground by peering intently at the crista, she is part of a broader group of UW scientists conducting research into hair cell regeneration, including ISCRM Affiliate Faculty Members David Raible and Jennifer Stone.
Already, the NIH grant for Dr. Bermingham-McDonogh’s lab points to the profound benefits of investing in novel research, as an early-stage award becomes a springboard to major funding that is now supporting a forward-thinking effort to ultimately ease the massive human and economic toll of a growing health crisis.
“Whatever we find is really important,” says Dr. Bermingham-McDonogh. “Because it tells us something about the hair cells, and it tells us something about the structure of an organ that hasn’t been studied closely. The long-term goal is to produce a body of data that takes us another step toward someday reducing the number of people suffering from falls.”